This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long term objective of our research program is to understand the mechanisms that casue type 2 diabetes mellitus (T2DM) in relatively young Mexican Americans in order to develop better approaches to prediction, prevention and early treatment of the disease. The specific objective of the BetaGene Study that this application supports is to identify genes that predispose to T2DM and understand how those genes contribute to development of the diabetes. In the first five years of the study, we carefully phenotyped 209 Mexican American women at high risk for T2DM becasue they had gestational diabetes mellitus (GDM), along with 567 of their siblings, 298 of their first cousins and 150 women who did not have GDM. We found that variation in three genes, hepatacyte neclear factor 4a (HNF4A, SNP rs2144908), transcription factor 7 like-2 (TCF7L2, rs12255372) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2, SNP rs11705701), that have been associated with T2DM in other studies also have weak associations with poor pancreatic B-cell functions, a main cause of T2DM on cross-sectional analysis in the BetaGene cohort. We have preliminary data forHNF4A showing that ther is a stronger association between the genetic variation and rates of change in B-cell funstion over time than can be detected by cross-sectional analysis alone. Based on that observation and our prior studies of the physilogy of T2DM after GDM, WE HPOTHESIZE THAT T2DM GENES CONTRIBUTE TO DIESEASE RISK INFLUENCING RATES OF CHANGE IN B-CELL COMPENSATION FOR INSULIN RESISTANCE. To test that hypothesis, we propse to call back ~400 individuals in the BetaGene cohort with specific genotypes for variants HNF4A TCF7L2 and IGF2BP2 and re-test them to determine changes in B-cell function and two other important T2DM-related phenotypes, insulin resistance and body fat. We will also characterize dietary intake and physical activity.The tree primary data analyses will compare rates of change in B-cell sompensation (the disposition indez from intravenous glucose tolerance tests) between genotypes for each of the three genes of interest. Secondary analysis will examine (a) potential influences of the genes on the genes on B-cell compensation in response to oralglucose and (b) potential interactions among genetic effects on change in B-cell function and insulin resistance, obesity, dietary intake and physical activity. We will also conduct exploratory analyses on other diabetes risk genes as new information on them becomes available. The results of these studies will provide new and unique information about the degree to which and mechanisms by which specific genes contribute to the pathophysiology of T2DM in Mexican Americans. The result will help direct basic research into genetic mechanisms for diabetes at the appropriate physiological abnormalities. The result wil also help us develop better approaches to predicting and prevention T2DM.